1. Field of the Invention
The present invention relates to the field of treating patients having gastrointestinal ulcers or gastritis caused by microbial infection.
2. Description of the Background Art
The stomach's infection with the germ Heliobacter pylori (H.p.) is one of the most frequent infectious diseases in the world; in developing countries, more than 80% of the population is already infected with H.p. during childhood.
In the past, chronic gastritis with prolonged dyspeptic symptoms in the upper stomach, the peptic ulcer, duodenal ulcer (UD) and ventral ulcer (UV) with pain in the upper stomach after meals or epigastric pain on empty stomach being a syndrome with unclear etiology. Its pathogenesis had not been clarified in detail. Generally, it can still be said today that there is no peptic ulcer without proteolytic gastric acid. Differential-diagnostic measures usually succeed in differentiating the peptic formation of ulcers from psychogenic gastrointestinal malfunctions. The final diagnosis depends on X-ray results.
Bismuth Salts
Initially, treatment was based on administering antacids, such as magnesium or aluminum compounds, calcium carbonates, alkaline bismuth salts, e.g. bismuth aluminate, colloidal bismuth salts. A high relapse rate of over 80% and side effects, such as the rebound effect of acid secretion, deposits of aluminum and bismuth salts in the tissue to bismuth nephropathy, and bismuth encephalopathy forced the medical field to pursue new paths.
Surgery
The selective proximal vagotomy with surgical exclusion of the appropriate vagus branches or the acid-producing stomach sections in the case of relapsing stomach duodenal ulcers was another medical path that usually went nowhere. The relapse rate usually did not change with this serious surgical procedure.
H.sub.2 -Receptor Antagonists
In acid secretion, H.sub.2 -receptors are involved. The introduction of the H.sub.2 -receptor antagonists Cimetidine (Tagametg.RTM.) in 1977, and then Ranitidine (Zantic.RTM., Sostril.TM.) represented a milestone in medicinal ulcer therapy. This led to rapid pain elimination with the healing of UD and UV. Side effects of long-term therapy, such as infectious diarrhea, persistent hypergastrinemia with germ settlements on the antacid stomach lumen and nitrosamine formation, had to be accepted. Despite progress in acute therapy and the short-term prophylaxis of peptic lesions, the course of ulcers and the relapse rate has not been influenced by the H.sub.2 -receptor antagonists.
Inhibitors of the Proton Pump
The currently most potent molecule in the stemming of gastric acid is Omeprazol (Antrag.RTM.). It specifically blocks the H.sup.+ /K.sup.30 adenosinetriphosphatases (ATP) of the mucosa of the stomach and thus hinders acid secretion. A suspected disadvantage is that, under permanent hypergastrinemia during Omeprazol therapy, a hyperplasia of neuroendocrine cells occurs and can lead to carcinoid tumors.
The high effectiveness compared to the H.sub.2 -receptor antagonists, however, led to shorter treatment times at lower dosage (20 mg/day). The relapse rate remained unchanged.
Heliobacter Pylori Infection
Marshall et al. only succeeded in 1983-1985 to prove the connection between the infection and gastritis through the rediscovery and ability to cultivate the germ Campylobacter pylori and through an oral infection in a self-test. This way the actual pathogenic factor of the ulcer was recognized. Initially, the germ was gained from biopsies of the antrum and corpus mucous membrane. In vitro cultivation did not succeed until later.
Bacteriology
According to examinations conducted by C. S. Goodwin, in Perth, Australia, the spiral-shaped Campylobacter pylori has little in common with other Campylobacter types (different fat composition, different enzyme metabolism, different genetic set-up). Therefore, it had to be renamed Heliobacter pylori.
Morphology
A spiral bent gram-negative germ, rods with lophotric flagellate, so-called clusters. Culturing is successful from stomach biopsies (antrum) on accumulation and selective media under microaerobic conditions of 90% N.sub.2, 5% CO.sub.2, 5% O.sub.2 for 3-4 days.
Identification succeeds through additional proof of the enzymes oxidase, catalase, and urease. The germ is able to break down carbamide into ammonia in order to survive in an alkaline environment (cloud) in the acidic environment of the stomach.
Pathogenesis and Clinic
H.p. only occurs in humans and is transmitted fecal-orally. The pathogen infects and settles in the mucosa of the stomach.
Heliobacter heilmanni, a variation of H.p., can be found in nearly all cats, dogs, and pigs. It can be passed on to humans. Infected people can develop disorders ranging from ulcers to stomach carcinomas.
Pathogenic Factors of H.p.
Due to the flagellated clusters, H.p. is particularly mobile and excels through increased adherence to surface cells of the stomach epithelium. The mucous membrane is attacked by proteases of the germn. Vacuolizing cytokinin (VacA), which destroys the epithelium cells, is released.
With the ELISA test, H.p. IgG antibody levels can be proven over an extended period of time, even after the infection has subsided. This immune reaction leads in turn to tissue damage. After the infection, an acute B-gastritis type develops. When untreated, the gastritis becomes chronic, and duodenal and stomach ulcers occur.
This can then develop into an adenocarcinoma of the stomach. The World Health Organization (WHO) has included H.p. into Category 4--Cancerogenes. The germ is to be interpreted as a resistance-weakening factor, which promotes early digestion of the mucosa of the stomach through the hydrochloric-acidic proteolytically active gastric Juice.
Therapy
Modern ulcer therapy has two goals:
1. alleviation of pain PA1 2. prevent complications and relapse rate. PA1 Italian Triple Therapy: Clarithromycine and Metronidazol PA1 French Triple Therapy: Clarithromycine and Amoxicillin
Initially, the patient is interested in quick relief of the pain and less in fast healing, i.e. Heliobacter pylori eradication.
Reinfection
After an H.p. infection has healed, reinfection is to be avoided. Flies, e.g., can take on H.p. bacteria and excrete them in a form that is capable of living in their excreta. Foods must be covered, and general hygienic conditions must be improved as an important preventive measure.
Antibiotics Combination Therapy
After proof has been secured of H.p. following gastroscopy and removal of the mucosa of the stomach from the antrum or corpus, eradication of the germ through combination therapy is necessary. Serious H.p.-related forms of gastritis and underdevelopment should be treated in accordance with cancer prophylaxis--stomach carcinoma and lymphoma (MALT). Treatment turned out to be very difficult. Due to a high relapse rate, the mono- and dual-therapy was insufficient. For mono-therapy with bismuth compounds, and for dual-therapy with Amoxicillin and Omeprazol, the eradication rate was only between 35 and 60%.
Triple Therapy
Through the combination of bismuth, Amoxicillin and Metronidazol, healing was achieved for the first time in 85-95% of the cases after a 4-week treatment. The toxicity of this 3-fold combination, however, has not yet been clarified, especially when taking the long treatment time of 4 weeks into consideration.
Italian and French Triple Therapy
The triple therapy is a 7-day treatment with the proton pump inhibitor as well as two antibiotics.
The medication must be taken twice daily each in standard dosages. This means that the patient must take 12 tablets a day. Also, there are side effects of the antibiotics, especially diarrhea, taste changes, etc. An antibiotics resistance development is also disadvantageous. H.p. resistance to Metronidazol and Amoxicillin has already been found.
There remains an urgent need in the art for improved methods of treating gastrointestinal ulcers or gastritis caused by microbial infections.